Novel breakthrough in the treatment of sphingomyelinase deficiency

Dear Editor, Acid sphingomyelinase deficiency (ASMD), more commonly classified under the subtypes Niemann-Pick disease type A (NPD A) and Niemann-Pick disease type B (NPD B), is a primary lysosomal hydrolase defect that develops due to the deficiency of acid sphingomyelinase (ASM). When there is a lack of this enzyme, sphingomyelin builds up in the cells inducing damage to the tissues1. In a study conducted by McGovern et al2, 18 out of 103 patients with Niemann-Pick disease (NPD) died due to complications such as pneumonia, liver failure, and hemorrhage. Despite the alarming morbidity, supportive measures and lifestyle changes were the main conduits to managing this disease until recently. ASMD is caused by the deficiency of the enzyme ASM, which is encoded by the gene sphingomyelin phosphodiesterase 1. ASM-deficient NPD is passed down as an autosomal recessive trait, but several reports are present where it was present in heterozygous individuals as well1. ASM, found in lysosomes, takes part in membrane degradation. It primarily acts on sphingomyelin, which is a major constituent of the cell membrane and breaks it into ceramide. Because of ASMD, there is a build-up of sphingomyelin, procuring huge lipid-laden foam cells which results in the impairment of the proper functioning of organs. NPD A is characterized by a severe deficit of ASM. The accumulation of sphingomyelin in neurons causes neurodegeneration and typically death by 3 years of age. The organs most commonly affected are the liver, spleen, and lungs, culminating in hepatosplenomegaly and respiratory crisis. NPD B is generally considered the milder form of NPD A. By comparison, patients with the type B variant have organomegaly but no neurological manifestations1. Patients with NPD are recommended lifestyle interventions to suppress further exacerbation of the disease. Some of the current guidelines for the treatment of NPD are caution in contact sports to reduce the chances of spleen rupture, regular hepatic assessments, complete blood counts, chest radiographs for proper lung function, periodic testing for peripheral neuropathy and neuropsychology, ECGs, and lipid profiles to avoid heart complications3. As of date, no disease-specific drugs have been developed to cure NPD. However, enzyme replacement therapy with the recombinant human ASM, Olipudase Alfa-rpcp, under the brand name XENPOZYME, has been approved to treat ASMD. Xenpozyme is a recombinant protein that is administered intravenously. It works by replacing the defective enzyme ASM through enzyme replacement therapy and performing its function alternatively. Thus, it lessens the build-up of sphingomyelin just as the original enzyme would. The data obtained from the ASCEND and ASCEND-PEDS clinical trials, where people from different age groups having NPD A or NPD B were evaluated, indicates the promising results of the drug. In the ASCEND clinical trials, 36 patients were randomized to receive either Xenpozyme or a placebo for 52 weeks. Patients treated with Xenpozyme had a 22% improvement in lung’s diffusing capacity for carbon monoxide (DLco) and had a reduction in spleen size by 39.5%, compared with a 3% DLco improvement and 0.5% increase in spleen size for the patients in the placebo group4. In the ASCEND-Peds trial, 20 pediatric patients received Xenpozyme. After 52 weeks, there was a 33% increase in the DLco and a decrease in spleen size by 49% compared with baseline4. In another study, five adult patients with chronic ASMD were given escalating doses of olipudase alfa intravenously for 26 weeks. The follow-up data that were analyzed 30 months after the trials stated that there was a 47.3% and a 35.6% decrease in the spleen and liver size as compared with the baseline. The DLco also improved to 67.1% from 53.2%5. Headaches, nasopharyngitis, URTIs, coughs, urticaria, and anaphylactic reactions were the noted side-effects seen in the patients present in ASCENDS Trial whereas, in the ASCEND-PEDS trial, pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, upper respiratory tract infections, contusion, abdominal pain, nasal congestion, rash, urticaria, and epistaxis were the reported adverse effects4. Xenpozyme is currently the only approved drug for ASMD. Although more data is needed, the approval of this novel drug has raised optimism and hope to provide better treatment for patients suffering from ASMD. Ethical approval Not applicable. Sources of funding None. Authors’ contribution W.S. : conceptualization, writing – original draft, final approval and agreeing to the accuracy of the work. T.S.: final approval and agreeing to accuracy of work. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) None. Guarantor Wania Sultan and Tasmiyah Siddiqui.